The lining of blood vessels (endothelium) releases a variety of substances that cause the smooth muscle to relax. One important substance is known as nitric oxide. We have previously shown that nitric oxide activity in the blood vessels is reduced in patients who are exposed to risk factors for heart disease such as high blood pressure, high cholesterol level, diabetes, aging, etc. In these studies we investigated whether this abnormality is restricted to one receptor type on the endothelium. We therefore compared the effects of substance P with acetylcholine, two agents that are known to stimulate the endothelium into releasing nitric oxide. Patients who had atherosclerosis and those with risk factors for atherosclerosis had depressed responses both in the heart circulation and in their leg circulation in response to both of these agents. Also, their ability to release nitric oxide at rest was depressed. We also examined the activity of nitric oxide at rest and after stimulation with acetylcholine and substance P in saphenous vein grafts of patients who have previously undergone bypass surgery. Saphenous vein grafts had reduced activity of nitric oxide at rest and after stimulation with agents able to release nitric oxide and donors of nitric oxide such as nitroprusside. This might explain why atherosclerosis progresses more rapidly in vein grafts than in arterial conduits.